ID   ACER_DROME              Reviewed;         630 AA.
AC   Q9VLJ6; Q24222;
DT   30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   27-MAR-2024, entry version 160.
DE   RecName: Full=Angiotensin-converting enzyme-related protein;
DE            EC=3.4.15.1;
DE   Flags: Precursor;
GN   Name=Acer; ORFNames=CG10593;
OS   Drosophila melanogaster (Fruit fly).
OC   Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC   Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC   Drosophilidae; Drosophila; Sophophora.
OX   NCBI_TaxID=7227;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE.
RX   PubMed=8973330; DOI=10.1016/s0378-1119(96)00503-3;
RA   Taylor C.A.M., Coates D., Shirras A.D.;
RT   "The Acer gene of Drosophila codes for an angiotensin-converting enzyme
RT   homologue.";
RL   Gene 181:191-197(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Berkeley;
RX   PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA   Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA   Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA   George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA   Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA   Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA   Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA   An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA   Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA   Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA   Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA   Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA   Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA   Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA   Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA   Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA   Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA   Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA   Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA   Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA   Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA   Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA   McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA   Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA   Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA   Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA   Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA   Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA   Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA   Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA   Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA   Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA   Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA   Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA   Venter J.C.;
RT   "The genome sequence of Drosophila melanogaster.";
RL   Science 287:2185-2195(2000).
RN   [3]
RP   GENOME REANNOTATION.
RC   STRAIN=Berkeley;
RX   PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA   Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA   Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA   Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA   Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA   Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA   Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT   "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT   review.";
RL   Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Berkeley; TISSUE=Embryo;
RX   PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA   Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA   Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA   Celniker S.E.;
RT   "A Drosophila full-length cDNA resource.";
RL   Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN   [5]
RP   BIOPHYSICOCHEMICAL PROPERTIES, GLYCOSYLATION, SUBCELLULAR LOCATION, AND
RP   ACTIVITY REGULATION.
RX   PubMed=9839949; DOI=10.1046/j.1432-1327.1998.2570599.x;
RA   Houard X., Williams T.A., Michaud A., Dani P., Isaac R.E., Shirras A.D.,
RA   Coates D., Corvol P.;
RT   "The Drosophila melanogaster-related angiotensin-I-converting enzymes Acer
RT   and Ance -- distinct enzymic characteristics and alternative expression
RT   during pupal development.";
RL   Eur. J. Biochem. 257:599-606(1998).
RN   [6]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=12075344; DOI=10.1038/nature00786;
RA   Crackower M.A., Sarao R., Oudit G.Y., Yagil C., Kozieradzki I.,
RA   Scanga S.E., Oliveira-dos-Santos A.J., da Costa J., Zhang L., Pei Y.,
RA   Scholey J., Ferrario C.M., Manoukian A.S., Chappell M.C., Backx P.H.,
RA   Yagil Y., Penninger J.M.;
RT   "Angiotensin-converting enzyme 2 is an essential regulator of heart
RT   function.";
RL   Nature 417:822-828(2002).
CC   -!- FUNCTION: May be involved in the specific maturation or degradation of
CC       a number of bioactive peptides. May have a role in the specification of
CC       heart progenitors. {ECO:0000269|PubMed:12075344}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Release of a C-terminal dipeptide, oligopeptide-|-Xaa-Yaa,
CC         when Xaa is not Pro, and Yaa is neither Asp nor Glu. Thus, conversion
CC         of angiotensin I to angiotensin II, with increase in vasoconstrictor
CC         activity, but no action on angiotensin II.; EC=3.4.15.1;
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC   -!- ACTIVITY REGULATION: Inhibited by captopril, lisinopril,
CC       trandolaprilat, fosinoprilat and enalaprilat.
CC       {ECO:0000269|PubMed:9839949}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=1.2 mM for Hip-His-Leu {ECO:0000269|PubMed:9839949};
CC         KM=4.35 mM for Hip-His-Leu-NH(2) {ECO:0000269|PubMed:9839949};
CC         KM=40.6 uM for (Leu5)enkephalin {ECO:0000269|PubMed:9839949};
CC         KM=949 uM for (Leu5)enkephalinamide {ECO:0000269|PubMed:9839949};
CC       pH dependence:
CC         Optimum pH is 8.6. {ECO:0000269|PubMed:9839949};
CC   -!- SUBCELLULAR LOCATION: Secreted, extracellular space
CC       {ECO:0000269|PubMed:9839949}.
CC   -!- DEVELOPMENTAL STAGE: Expressed in presumptive heart cells during dorsal
CC       closure. {ECO:0000269|PubMed:8973330}.
CC   -!- PTM: Glycosylated. {ECO:0000269|PubMed:9839949}.
CC   -!- DISRUPTION PHENOTYPE: Defective heart morphogenesis leading to
CC       lethality. {ECO:0000269|PubMed:12075344}.
CC   -!- MISCELLANEOUS: In contrast to ance, does not hydrolyze angiotensin I.
CC   -!- SIMILARITY: Belongs to the peptidase M2 family. {ECO:0000305}.
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DR   EMBL; X96913; CAA65632.1; -; mRNA.
DR   EMBL; AE014134; AAF52693.1; -; Genomic_DNA.
DR   EMBL; AY051750; AAK93174.1; -; mRNA.
DR   PIR; JC5374; JC5374.
DR   RefSeq; NP_001260258.1; NM_001273329.1.
DR   RefSeq; NP_477195.1; NM_057847.4.
DR   AlphaFoldDB; Q9VLJ6; -.
DR   SMR; Q9VLJ6; -.
DR   BioGRID; 60309; 2.
DR   IntAct; Q9VLJ6; 2.
DR   STRING; 7227.FBpp0305608; -.
DR   MEROPS; M02.002; -.
DR   PaxDb; 7227-FBpp0305608; -.
DR   DNASU; 34189; -.
DR   EnsemblMetazoa; FBtr0079685; FBpp0079297; FBgn0016122.
DR   EnsemblMetazoa; FBtr0333416; FBpp0305608; FBgn0016122.
DR   GeneID; 34189; -.
DR   KEGG; dme:Dmel_CG10593; -.
DR   AGR; FB:FBgn0016122; -.
DR   CTD; 34189; -.
DR   FlyBase; FBgn0016122; Acer.
DR   VEuPathDB; VectorBase:FBgn0016122; -.
DR   eggNOG; KOG3690; Eukaryota.
DR   GeneTree; ENSGT00940000163600; -.
DR   HOGENOM; CLU_014364_3_3_1; -.
DR   InParanoid; Q9VLJ6; -.
DR   OMA; FYRQIHG; -.
DR   OrthoDB; 2898149at2759; -.
DR   PhylomeDB; Q9VLJ6; -.
DR   Reactome; R-DME-2022377; Metabolism of Angiotensinogen to Angiotensins.
DR   SABIO-RK; Q9VLJ6; -.
DR   BioGRID-ORCS; 34189; 0 hits in 3 CRISPR screens.
DR   GenomeRNAi; 34189; -.
DR   PRO; PR:Q9VLJ6; -.
DR   Proteomes; UP000000803; Chromosome 2L.
DR   Bgee; FBgn0016122; Expressed in head capsule and 33 other cell types or tissues.
DR   ExpressionAtlas; Q9VLJ6; baseline and differential.
DR   GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; IDA:FlyBase.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0004180; F:carboxypeptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0004222; F:metalloendopeptidase activity; ISS:FlyBase.
DR   GO; GO:0008237; F:metallopeptidase activity; IBA:GO_Central.
DR   GO; GO:0008241; F:peptidyl-dipeptidase activity; IDA:FlyBase.
DR   GO; GO:0008270; F:zinc ion binding; ISM:FlyBase.
DR   GO; GO:0007507; P:heart development; IMP:UniProtKB.
DR   GO; GO:0003007; P:heart morphogenesis; IMP:FlyBase.
DR   GO; GO:0045938; P:positive regulation of circadian sleep/wake cycle, sleep; IMP:FlyBase.
DR   GO; GO:0006508; P:proteolysis; IDA:FlyBase.
DR   GO; GO:0002027; P:regulation of heart rate; IMP:FlyBase.
DR   CDD; cd06461; M2_ACE; 1.
DR   Gene3D; 1.10.1370.30; -; 1.
DR   InterPro; IPR001548; Peptidase_M2.
DR   PANTHER; PTHR10514; ANGIOTENSIN-CONVERTING ENZYME; 1.
DR   PANTHER; PTHR10514:SF27; ANGIOTENSIN-CONVERTING ENZYME; 1.
DR   Pfam; PF01401; Peptidase_M2; 1.
DR   PRINTS; PR00791; PEPDIPTASEA.
DR   SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1.
DR   PROSITE; PS52011; PEPTIDASE_M2; 1.
DR   PROSITE; PS00142; ZINC_PROTEASE; 1.
DR   Genevisible; Q9VLJ6; DM.
PE   1: Evidence at protein level;
KW   Carboxypeptidase; Disulfide bond; Glycoprotein; Hydrolase; Metal-binding;
KW   Metalloprotease; Protease; Reference proteome; Secreted; Signal; Zinc.
FT   SIGNAL          1..22
FT                   /evidence="ECO:0000255"
FT   CHAIN           23..630
FT                   /note="Angiotensin-converting enzyme-related protein"
FT                   /id="PRO_0000028564"
FT   DOMAIN          28..615
FT                   /note="Peptidase M2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   ACT_SITE        376
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   ACT_SITE        505
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   BINDING         375
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   BINDING         379
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   BINDING         403
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   DISULFID        142..150
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   DISULFID        344..362
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   DISULFID        530..548
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01355"
FT   CONFLICT        236
FT                   /note="F -> L (in Ref. 1; CAA65632)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        341
FT                   /note="H -> Q (in Ref. 1; CAA65632)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        528
FT                   /note="A -> V (in Ref. 1; CAA65632)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   630 AA;  73057 MW;  6D9355EB57773289 CRC64;
     MGACNITVLL LVIMLWLPHG LSMGNSCSAS VLEARRFFEL ENEQLRRRFH EEFLSGYNYN
     TNVTEANRQA MIEVYARNAE LNKRLAQQIK SSDYVQSEDA DIRRQAEHLS KLGASALNAD
     DYLALQNAIS SMQTNYATAT VCSYTNRSDC SLTLEPHIQE RLSHSRDPAE LAWYWREWHD
     KSGTPMRQNF AEYVRLTRKA SQLNGHRSYA DYWVQFYEDP DFERQLDATF KQLLPFYRQL
     HGYVRFRLRQ HYGPDVMPAE GNIPISLLGN MWGQSWNELL DLFTPYPEKP FVDVKAEMEK
     QGYTVQKLFE LGDQFFQSLG MRALPPSFWN LSVLTRPDDR HVVCHASAWD FYQDSDVRIK
     MCTEVDSHYF YVVHHELGHI QYYLQYEQQP AVYRGAPNPG FHEAVGDVIA LSVMSAKHLK
     AIGLIENGRL DEKSRINQLF KQALSKIVFL PFGYAVDKYR YAVFRNELDE SQWNCGFWQM
     RSEFGGVEPP VFRTEKDFDP PAKYHIDADV EYLRYFAAHI FQFQFHKALC RKAGQYAPNN
     SRLTLDNCDI FGSKAAGRSL SQFLSKGNSR HWKEVLEEFT GETEMDPAAL LEYFEPLYQW
     LKQENSRLGV PLGWGPTDKI PSDCCGTFST
//